Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies are associated with certain immunodeficiencies in humans. Enzon will use patented methodology to prepare therapeutic modifications of ADA and PNP. The procedure consists of attachment of monomethoxypolyethylene glycol (PEG) in sufficient amounts to enzymes to produce conjugates that are essentially nonimmunogenic and show extended circulating lives in blood. PEG-ADA and PEG-PNP will be tested for nonimmunogenicity, extended and repetitive blood circulating life, and toxicity (short-term, long-term, LD50 and maximum tolerated dose). Blood sera will be analyzed for decrease in substrate for each enzyme. We expect, based on our extensive experience with other PEG-enzymes, that PEG-ADA and PEG-PNP will be effective in lowering the levels of their respective substrates and will show little or no toxicity. Although enzymes - the body's natural catalysts - have major potential as therapeutic agents to treat many clinical problems, their use has been severely limited by the twin problems of immunogenicity and short blood life. The PEG process eliminates these problems and allows enzymes from the most inexpensive sources to be used in therapy. Because of their specificity of action, side effects should be limited. In addition, PEG-enzymes may provide therapy for diseases for which no drug is currently available. The potential commercial application of PEG-enzymes is enormous. Enzon estimates eventual sales of all PEG-enzymes in the hundreds of millions of dollars per year. The enzymes we will evaluate here are the forerunners of a new mode of therapy.